Interferon‑γ induced PD‑L1 expression and soluble PD‑L1 production in gastric cancer

Imai,Yushi; Chiba,Tetsuhiro; Kondo,Takayuki; Kanzaki,Hiroaki; Kanayama,Kengo; Ao,Junjie; Kojima,Ryuta; Kusakabe,Yuko; Nakamura,Masato; Saito,Tomoko; Nakagawa,Ryo; Suzuki,Eiichiro; Nakamoto,Shingo; Muroyama,Ryosuke; Tawada,Akinobu; Matsumura,Tomoaki; Nakagawa,Tomoo; Kato,Jun; Kotani,Ai; Matsubara,Hisahiro; Kato,Naoya

doi:10.3892/ol.2020.11757

Interferon‑γ induced PD‑L1 expression and soluble PD‑L1 production in gastric cancer

Authors:
- Yushi Imai
- Tetsuhiro Chiba
- Takayuki Kondo
- Hiroaki Kanzaki
- Kengo Kanayama
- Junjie Ao
- Ryuta Kojima
- Yuko Kusakabe
- Masato Nakamura
- Tomoko Saito
- Ryo Nakagawa
- Eiichiro Suzuki
- Shingo Nakamoto
- Ryosuke Muroyama
- Akinobu Tawada
- Tomoaki Matsumura
- Tomoo Nakagawa
- Jun Kato
- Ai Kotani
- Hisahiro Matsubara
- Naoya Kato
View Affiliations

Affiliations: Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan, Department of Molecular Virology, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan, Division of Hematological Malignancy, Institute of Medical Sciences, Tokai University, Isehara, Kanagawa 259‑1193, Japan, Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan
Published online on: June 19, 2020 https://doi.org/10.3892/ol.2020.11757
Pages: 2161-2168
Copyright: © Imai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Programmed death‑ligand 1 (PD‑L1) plays an essential role in tumor cell escape from anti‑tumor immunity in various types of cancer, including gastric cancer (GC). The present study investigated the intracellular and membrane‑bound expression of PD‑L1 in the GC cell lines MKN1, MKN74, KATO III and OCUM‑1. Furthermore, soluble PD‑L1 (sPD‑L1) level in the supernatant of GC cells and the serum of patients with GC and healthy controls was determined by ELISA. Interferon (IFN)‑γ treatment of cells resulted in increased cytoplasmic expression of PD‑L1 in GC cells in a dose‑dependent manner, except for MKN74 cells; however, there was no association between tumor necrosis factor‑α treatment and enhanced PD‑L1 expression. Concordant with these findings, results from flow cytometry analysis demonstrated that membrane‑bound PD‑L1 expression was also increased following GC cell treatment with IFN‑γ in a dose‑dependent manner. In addition, significant sPD‑L1 overproduction was observed only in the culture supernatant of OCUM‑1 cells. Serum level of sPD‑L1 was significantly increased in patients with GC, in particular in stage IV patients, compared with healthy controls. In conclusion, the present study demonstrated that IFN‑γ treatment increased the intracellular and membrane‑bound PD‑L1 expression in GC cells. In addition, sPD‑L1 was detected not only in the supernatant of GC cells but also in the serum of patients with GC. Further investigation on the underlying mechanism of regulation of PD‑L1 expression and sPD‑L1 production is required.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer Statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
2	Khasag O, Boldbaatar G, Tegshee T, Duger D, Dashdorj A, Uchida T, Matsuhisa T and Yamaoka Y: The prevalence of helicobacter pylori infection and other risk factors among mongolian dyspeptic patients who have a high incidence and mortality rate of gastric cancer. Gut Pathog. 10:142018. View Article : Google Scholar : PubMed/NCBI
3	Shiota S, Murakawi K, Suzuki R, Fujioka T and Yamaoka Y: Helicobacter pylori infection in Japan. Expert Rev Gastroenterol Hepatol. 7:35–40. 2013. View Article : Google Scholar : PubMed/NCBI
4	Selim JH, Shaheen S, Sheu WC and Hsueh CT: Targeted and novel therapy in advanced gastric cancer. Exp Hematol Oncol. 8:252019. View Article : Google Scholar : PubMed/NCBI
5	Karimi P, Islami F, Anandasabapathy S, Freedman ND and Kamangar F: Gastric cancer: Descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev. 23:700–713. 2014. View Article : Google Scholar : PubMed/NCBI
6	Wei SC, Duffy CR and Allison JP: Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8:1069–1086. 2018. View Article : Google Scholar : PubMed/NCBI
7	Schreiber RD, Old LJ and Smyth MJ: Cancer immunoediting: Integrating immunity's roles in cancer suppression and promotion. Science. 331:1565–1570. 2011. View Article : Google Scholar : PubMed/NCBI
8	Postow MA, Callahan MK and Wolchok JD: Immune checkpoint blockade in cancer therapy. J Clin Oncol. 33:1974–1982. 2015. View Article : Google Scholar : PubMed/NCBI
9	Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, et al: Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 390:2461–2471. 2017. View Article : Google Scholar : PubMed/NCBI
10	Keir ME, Francisco LM and Sharpe AH: PD-1 and its ligands in T-cell immunity. Curr Opin Immunol. 19:309–314. 2007. View Article : Google Scholar : PubMed/NCBI
11	Guan J, Lim KS, Mekhail T and Chang CC: Programmed death ligand-1 (PD-L1) expression in the programmed death receptor-1 (PD-1)/PD-L1 blockade: A key player against various cancers. Arch Pathol Lab Med. 141:851–861. 2017. View Article : Google Scholar : PubMed/NCBI
12	Nagato T, Ohkuri T, Ohara K, Hirata Y, Kishibe K, Komabayashi Y, Ueda S, Takahara M, Kumai T, Ishibashi K, et al: Programmed death-ligand 1 and its soluble form are highly expressed in nasal natural killer/T-cell lymphoma: A potential rationale for immunotherapy. Cancer Immunol Immunother. 66:877–890. 2017. View Article : Google Scholar : PubMed/NCBI
13	Chang B, Huang T, Wei H, Shen L, Zhu D, He W, Chen Q, Zhang H, Li Y, Huang R, et al: The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma. Cancer Immunol Immunother. 68:353–363. 2019. View Article : Google Scholar : PubMed/NCBI
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
15	Deng R, Zhang P, Liu W, Zeng X, Ma X, Shi L, Wang T, Yin Y, Chang W, Zhang P, et al: HDAC is indispensable for IFN-γ-induced B7-H1 expression in gastric cancer. Clin Epigenetics. 10:1532018. View Article : Google Scholar : PubMed/NCBI
16	Union for International Cancer Control, . Briely JD, Gospodarowicz MK and Wittekind CH: TNM Classification of Malignant Tumors. 8th. Wiley-Blackwell; Hoboken, NJ: 2017
17	Intlekofer AM and Thompson CB: At the bench: Preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol. 94:25–39. 2013. View Article : Google Scholar : PubMed/NCBI
18	Ishida Y, Agata Y, Shibahara K and Honjo T: Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11:3887–3895. 1992. View Article : Google Scholar : PubMed/NCBI
19	Ma J, Zheng B, Goswami S, Meng L, Zhang D, Cao C, Li T, Zhu F, Ma L, Zhang Z, et al: PD1^Hi CD8⁺ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma. J Immunother Cancer. 7:3312019. View Article : Google Scholar : PubMed/NCBI
20	Ishida M, Iwai Y, Tanaka Y, Okazaki T, Freeman GJ, Minato N and Honjo T: Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunol Lett. 84:57–62. 2002. View Article : Google Scholar : PubMed/NCBI
21	Francisco LM, Sage PT and Sharpe AH: The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 236:219–242. 2010. View Article : Google Scholar : PubMed/NCBI
22	Teng MW, Ngiow SF, Ribas A and Smyth MJ: Classifying cancers based on t-cell infiltration and PD-L1. Cancer Res. 75:2139–2145. 2015. View Article : Google Scholar : PubMed/NCBI
23	Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V and Chouaib S: PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 211:781–790. 2014. View Article : Google Scholar : PubMed/NCBI
24	Darvin P, Toor SM, Sasidharan Nair V and Elkord E: Immune checkpoint inhibitors: Recent progress and potential biomarkers. Exp Mol Med. 50:1–11. 2018. View Article : Google Scholar : PubMed/NCBI
25	Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG and Xu N: Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 108:19–24. 2006. View Article : Google Scholar : PubMed/NCBI
26	Sun C, Mezzadra R and Schumacher TN: Regulation and function of the PD-L1 checkpoint. Immunity. 48:434–452. 2018. View Article : Google Scholar : PubMed/NCBI
27	Cha JH, Chan LC, Li CW, Hsu JL and Hung MC: Mechanisms controlling PD-L1 expression in cancer. Mol Cell. 76:359–370. 2019. View Article : Google Scholar : PubMed/NCBI
28	Shigemori T, Toiyama Y, Okugawa Y, Yamamoto A, Yin C, Narumi A, Ichikawa T, Ide S, Shimura T, Fujikawa H, et al: Soluble PD-L1 expression in circulation as a predictive marker for recurrence and prognosis in gastric cancer: Direct comparison of the clinical burden between tissue and serum PD-L1 expression. Ann Surg Oncol. 26:876–883. 2019. View Article : Google Scholar : PubMed/NCBI
29	Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, Wu X, Ma J, Zhou M, Li X, et al: Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 18:102019. View Article : Google Scholar : PubMed/NCBI
30	Mimura K, Teh JL, Okayama H, Shiraishi K, Kua LF, Koh V, Smoot DT, Ashktorab H, Oike T, Suzuki Y, et al: PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Cancer Sci. 109:43–53. 2018. View Article : Google Scholar : PubMed/NCBI
31	Chen J, Feng Y, Lu L, Wang H, Dai L, Li Y and Zhang P: Interferon-gamma-induced PD-L1 surface expression on human oral squamous carcinoma via PKD2 signal pathway. Immunobiology. 217:385–393. 2012. View Article : Google Scholar : PubMed/NCBI
32	Clark CA, Gupta HB and Curiel TJ: Tumor cell-intrinsic CD274/PD-L1: A novel metabolic balancing act with clinical potential. Autophagy. 13:987–988. 2017. View Article : Google Scholar : PubMed/NCBI
33	Qu QX, Xie F, Huang Q and Zhang XG: Membranous and cytoplasmic expression of PD-L1 in ovarian cancer cells. Cell Physiol Biochem. 43:1893–1906. 2017. View Article : Google Scholar : PubMed/NCBI
34	Aydin D, Bilici A, Yavuzer D, Kefeli U, Tan A, Ercelep O, Mert A, Yuksel S, Ozcelik M, Isik D, et al: Prognostic significance of ADAM17 expression in patients with gastric cancer who underwent curative gastrectomy. Clin Transl Oncol. 17:604–611. 2015. View Article : Google Scholar : PubMed/NCBI
35	Chen Y, Wang Q, Shi B, Xu P, Hu Z, Bai L and Zhang X: Development of a sandwich ELISA for evaluating soluble PD-L1 (CD274) in human sera of different ages as well as supernatants of PD-L1+ cell lines. Cytokine. 56:231–238. 2011. View Article : Google Scholar : PubMed/NCBI
36	Zhou J, Mahoney KM, Giobbie-Hurder A, Zhao F, Lee S, Liao X, Rodig S, Li J, Wu X, Butterfield LH, et al: Soluble PD-L1 as a biomarker in malignant melanoma treated with checkpoint blockade. Cancer Immunol Res. 5:480–492. 2017. View Article : Google Scholar : PubMed/NCBI
37	Zhu X and Lang J: Soluble PD-1 and PD-L1: Predictive and prognostic significance in cancer. Oncotarget. 8:97671–97682. 2017. View Article : Google Scholar : PubMed/NCBI
38	Gong B, Kiyotani K, Sakata S, Nagano S, Kumehara S, Baba S, Besse B, Yanagitani N, Friboulet L, Nishio M, et al: Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer. J Exp Med. 216:982–1000. 2019. View Article : Google Scholar : PubMed/NCBI
39	Frigola X, Inman BA, Krco CJ, Liu X, Harrington SM, Bulur PA, Dietz AB, Dong H and Kwon ED: Soluble B7-H1: Differences in production between dendritic cells and T cells. Immunol Lett. 142:78–82. 2012. View Article : Google Scholar : PubMed/NCBI
40	Frigola X, Inman BA, Lohse CM, Krco CJ, Cheville JC, Thompson RH, Leibovich B, Blute ML, Dong H and Kwon ED: Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin Cancer Res. 17:1915–1923. 2011. View Article : Google Scholar : PubMed/NCBI
41	Rossille D, Azzaoui I, Feldman AL, Maurer MJ, Labouré G, Parrens M, Pangault C, Habermann TM, Ansell SM, Link BK, et al: Soluble programmed death-ligand 1 as a prognostic biomarker for overall survival in patients with diffuse large B-cell lymphoma: A replication study and combined analysis of 508 patients. Leukemia. 31:988–991. 2017. View Article : Google Scholar : PubMed/NCBI
42	Finkelmeier F, Canli Ö, Tal A, Pleli T, Trojan J, Schmidt M, Kronenberger B, Zeuzem S, Piiper A, Greten FR and Waidmann O: High levels of the soluble programmed death-ligand (sPD-L1) identify hepatocellular carcinoma patients with a poor prognosis. Eur J Cancer. 59:152–159. 2016. View Article : Google Scholar : PubMed/NCBI
43	Ito M, Oshima Y, Yajima S, Suzuki T, Nanami T, Shiratori F, Funahashi K, Nemoto T and Shimada H: Is high serum programmed death ligand 1 level a risk factor for poor survival in patients with gastric cancer? Ann Gastroenterol Surg. 2:313–318. 2018. View Article : Google Scholar : PubMed/NCBI
44	Zheng Z, Bu Z, Liu X, Zhang L, Li Z, Wu A, Wu X, Cheng X, Xing X, Du H, et al: Level of circulating PD-L1 expression in patients with advanced gastric cancer and its clinical implications. Chin J Cancer Res. 26:104–111. 2014.PubMed/NCBI